Showing papers in "Clinical Pharmacokinectics in 1998"
TL;DR: T careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential, because the smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences.
Abstract: The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activities of substrates. Whenever 2 or more drugs are administered concurrently, the possibility of drug interactions exists. The ability of a single CYP to metabolise multiple substrates is responsible for a large number of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induction of several human CYPs following long term drug treatment. The mechanisms of CYP inhibition can be divided into 3 categories: (a) reversible inhibition; (b) quasi-irreversible inhibition; and (c) irreversible inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve only the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are generally irreversible or quasi-irreversible inhibitors. Irreversible and quasi-irreversible inhibition require at least one cycle of the CYP catalytic process. Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screening tools to predict the potential for in vivo drug interaction. Although it is easy to determine in vitro metabolic drug interactions, the proper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles. From the viewpoint of drug therapy, to avoid potential drug-drug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-mediated metabolism represents a major route of elimination of many drugs, which can compete for the same CYP enzyme. The clinical significance of a metabolic drug interaction depends on the magnitude of the change in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the drug. The smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential.
816 citations
TL;DR: The pharmacokinetics of patients with renal transplants compared with those of healthy individuals were similar after oral mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined.
Abstract: The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN
780 citations
TL;DR: The large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals.
Abstract: Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha 1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600 mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h. In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent and sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.
454 citations
TL;DR: A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated and a proposed site of action for nonsteroidal anti-inflammatory drugs is proposed.
Abstract: Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2 arylpropionic acid (2-APA) class. A common structural feature of 2-APANSAIDs is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its pharmacokinetics. Substantial unidirectional inversion of the R-(-) to the S-(+) enantiomer occurs and thus, data generated using nonstereospecific assays may not be extrapolated to explain the disposition of the individual enantiomers. The absorption of ibuprofen is rapid and complete when given orally. The area under the plasma concentration-time curve (AUC) of ibuprofen is dose-dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to plasma albumin. At doses greater than 600mg there is an increase in the unbound fraction of the drug, leading to an increased clearance of ibuprofen and a reduced AUC of the total drug. Substantial concentrations of ibuprofen are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Ibuprofen is eliminated following biotransformation to glucuronide conjugate metabolites that are excreted in urine, with little of the drug being eliminated unchanged. The excretion of conjugates may be tied to renal function and the accumulation of conjugates occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in substantial concentrations into breast milk. Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and methotrexate. A relationship between ibuprofen plasma concentrations and analgesic and antipyretic effects has been elucidated.
406 citations
TL;DR: A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes, and the reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion.
Abstract: A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations. Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the 'oxygen diffusion barrier' hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion. Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.
284 citations
TL;DR: While pharmacokinetic changes in the elderly are usually well characterised, pharmacodynamic changes are understood only in the most preliminary way and are still an area of investigation.
Abstract: Age-related changes in pharmacokinetics principally affect drug absorption, distribution, metabolism and elimination. Changes in pharmacodynamics are primarily seen in the cardiovascular and neuroendocrine system. Age-dependent changes in the kinetics and dynamics of drugs acting on the cardiovascular system and central nervous system are common, and this review, while by no means exhaustive of the effects of drugs on all organ systems, is reflective of the principles and gives examples of the effects of age on these 2 major systems. While pharmacokinetic changes in the elderly are usually well characterised, pharmacodynamic changes are understood only in the most preliminary way. There has been relatively little research in this area of geriatric clinical pharmacology, and pharmacodynamic changes are still an area of investigation.
257 citations
TL;DR: Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipop protein and plasma triglycerides, which are often accompanied by reductions in high densitylipoprotein (HDL) levels.
Abstract: Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein(a), fibrinogen and uric acid. As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment. The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate. Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.
245 citations
TL;DR: Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is crucial to optimising the pharmacodynamic response and outcome.
Abstract: Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.
201 citations
TL;DR: Several chemically unrelated agents has been developed and introduced in the past decade, to supplement the earlier antidepressants, as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine, which may explain the individual variability with all these drugs.
Abstract: Several chemically unrelated agents has been developed and introduced in the past decade, to supplement the earlier antidepressants. These include inhibitors of the reuptake of serotonin [the selective serotonin reuptake inhibitors (SSRI)] or noradrenaline (reboxetine) or both (milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. Like the earlier drugs, these newer antidepressants are almost totally biotransformed before excretion, except for milnacipran whose clearance appears to be due equally to both urinary excretion and metabolism. Sometimes — as in the case of moclobemide — up to 20 metabolites have been identified in body fluids. In some cases, however, only a few metabolites have been detected, and a substantial proportion of the dose remains unaccounted for (e.g. fluoxetine and fluvoxamine). Metabolism generally proceeds through sequential or parallel oxidative pathways. These may be affected to varying degrees by physiological and pathological factors and those mediated by cytochrome P450 (CYP) 2D6 and CYP2C19 through genetic polymorphism. Some are influenced by chirality (e.g. the dealkylation of citalopram and fluoxetine), although information on this aspect of disposition is still lacking for other drugs existing as racemates (e.g. mirtazepine and tianeptine) and milancipran, which is probably a mixture of 4 stereoisomers. Others again are saturable within the therapeutic range of doses (e.g. some pathways of metabolism of fluoxetine, fluvoxamine, nefazodone, paroxetine and venlafaxine). This may explain the individual variability with all these drugs which, from the pharmacokinetic point of view, is the same as with tricyclic agents. Our knowledge of the isoenzymes involved in the various oxidation pathways and their relevance for potential drug interactions varies from a considerable amount for most of the SSRI and nefazodone, to minimal for reboxetine and tianeptine. This information is useful for predicting the pharmacokinetic interactions mediated through inhibition of specific isoenzymes. This would be better appreciated if the enzymatic mechanisms involved in the biotransformation of the metabolite(s), and their role in drug interactions, were also known. This information is still lacking for some drugs, although metabolites may exhibit in vitro inhibitory potencies of similar to (paroxetine and its M2 metabolite as inhibitors of CYP2D6) or even greater than that of the parent drug (norfluoxetine is more potent than fluoxetine as an inhibitor of CYP3A3/4, and in view of the longer half-life (t1/2) of the metabolite the potential for interactions may persist for weeks after discontinuation of the parent drug). While we do know something about the biological activity of the metabolites of some of these drugs, we know very little about others. With few exceptions this knowledge refers only to the major metabolite(s) and regards the main in vitro effects as exerted by the parent drug. However, in vitro potency and selectivity may not translate directly into in vivo, and either major or minor metabolites may have characteristic in vitro and in vivo properties. For example, unlike the parent drug some minor ring-opened metabolites of moclobemide have monoamine oxidase-B inhibitory activity in the rat, and the nefazodone metabolite m-chlorophenyl-piperazine shows activity on 5-HT2C receptors in rats and humans. Data on the brain-to-blood partition of metabolites compared with their parent drug are available only in a few cases. They are still not known for the main metabolites of fluvoxamine, milnacipran, mirtazapine, moclobemide, nefazodone, paroxetine, reboxetine and venlafaxine, despite the fact that total blood concentrations do not always reflect the metabolite: parent drug ratio in brain. Thus, in most cases, we do not really know what part hepatic metabolism plays in the overall effect of the administered parent drug.
167 citations
TL;DR: The optimisation of antibiotic therapy in patients with CF includes increasing the dose of β-lactams by 20 to 30% and monitoring plasma concentrations of aminoglycosides and the appropriate dosage of quinolones has not been definitively established.
Abstract: There are many pathological changes in patients with cystic fibrosis (CF) which can lead to alterations in drug disposition.
161 citations
TL;DR: It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 μg/L, and marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy.
Abstract: Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.
TL;DR: Drug chronopharmacokinetic knowledge may be clinically relevant as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-hour scale and should be considered in specific cases related to patients, illness or the drug itself.
Abstract: Absorption, distribution, metabolism and elimination are influenced by many different physiological functions of the body which may vary with time of day. Thus, the pharmacokinetic parameters characterising these different steps, conventionally considered to be constant in time, depend on the moment of drug administration. Time of day has to be regarded as an additional variable influencing the kinetics of a drug. Chronokinetic studies have been reported for many drugs in an attempt to explain chronopharmacodynamic phenomena and demonstrate that the time of administration is a possible factor of variation in the kinetics of a drug. In this paper this is illustrated with the chronopharmacokinetics of cardiovascular and nonsteroidal anti-inflammatory drugs. Time-dependent changes in kinetics may proceed from circadian variations at each step, e.g. absorption, distribution, metabolism and elimination. Thus, circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such kinetic variations. New tools, such as new formulation procedures or pumps with constant or programmable delivery rates, now make it possible to deliver a drug at a definite time, or during a definite span of time and at a controlled rate in chronokinetic studies. Microdialysis would be of particular interest in chronopharmacological and chronokinetics studies, but, surprisingly, very few chronobiological studies have been conducted using this technique. With regard to new models and concepts in chronokinetics, pharmacokinetic-pharmacodynamic modelling may be useful, and modelling of the chronopharmacological patterns of drug response and kinetics have been attempted by some authors. Drug chronopharmacokinetic knowledge may be clinically relevant as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-hour scale. However, it seems reasonable to consider chronopharmacokinetic studies in specific cases related to patients, illness or the drug itself. When conducting a chronokinetic study it is not only necessary to take into account differences in the time of administration but to also have strict control of all other possible variables which are known to influence pharmacokinetic processes.
TL;DR: Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation and may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication.
Abstract: There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharmacokinetics and pharmacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred. It is postulated that hormonal fluctuations within the menstrual cycle phase may be a primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggest that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics or pharmacodynamics of drugs by altering properties, such as protein binding or the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited. Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication. Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharmacokinetics are limited and contradictory. Systematic investigations of specific pharmacokinetic and pharmacodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in a suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharmacokinetics and pharmacodynamics are needed.
TL;DR: The use of population pharmacokinetic models to store experiences about drugs in patients and to apply that experience to the care of new patients is examined, especially for bacterial and viral infections, cardiovascular therapy, and cancer and transplant situations.
Abstract: This article examines the use of population pharmacokinetic models to store experiences about drugs in patients and to apply that experience to the care of new patients. Population models are the Bayesian prior. For truly individualised therapy, it is necessary first to select a specific target goal, such as a desired serum or peripheral compartment concentration, and then to develop the dosage regimen individualised to best hit that target in that patient. One must monitor the behaviour of the drug by measuring serum concentrations or other responses, hopefully obtained at optimally chosen times, not only to see the raw results, but to also make an individualised (Bayesian posterior) model of how the drug is behaving in that patient. Only then can one see the relationship between the dose and the absorption, distribution, effect and elimination of the drug, and the patient's clinical sensitivity to it; one must always look at the patient. Only by looking at both the patient and the model can it be judged whether the target goal was correct or needs to be changed. The adjusted dosage regimen is again developed to hit that target most precisely starting with the very next dose, not just for some future steady state. Nonparametric population models have discrete, not continuous, parameter distributions. These lead naturally into the multiple model method of dosage design, specifically to hit a desired target with the greatest possible precision for whatever past experience and present data are available on that drug--a new feature for this goal-oriented, model-based, individualised drug therapy. As clinical versions of this new approach become available from several centers, it should lead to further improvements in patient care, especially for bacterial and viral infections, cardiovascular therapy, and cancer and transplant situations.
TL;DR: In this paper, a continuous infusion therapy with penicillins and cephalosporins has been proposed for Gram-negative infection in neutropenic patients with Gram-positive cocci.
Abstract: There are considerable laboratory data and information from animal and continuous culture in vitro models to support continuous infusion therapy for penicillins and cephalosporins, but, as yet, the only existing clinical data relate to cephalosporins. Penicillins do not exert concentration-dependent killing in the therapeutic range but have a post-antibiotic effect (PAE) against Gram-positive cocci but not Gram-negative rods. Animal models indicate the time (T) during which the serum concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen [T > MIC] determines outcomes. Pharmacokinetic studies in humans indicate that continuous infusion with penicillins is possible but there are no clinical data on efficacy. Cephalosporins have similar pharmacodynamic properties to penicillins; T > MIC determines outcome. Data related to ceftazidime indicate that the drug concentration at steady-state (Css) should exceed the pathogen MIC by > 1-fold and perhaps by 4- to 5-fold or more. Human pharmacokinetics of ceftazidime administered by continuous infusion to a wide variety of patient groups indicates that Css of > 20 mg/L can easily be achieved using conventional daily doses. Clinical data indicate increased effectiveness of a continuous regimen in neutropenic patients with Gram-negative infection. Furthermore cefuroxime administration by continuous infusion has resulted in lower doses and shorter course durations. Little is known of the pharmacodynamics of monobactams and there are few clinical data on continuous infusion therapy. Carbapenems have different pharmacodynamics to other beta-lactams as they have concentration-dependent killing and a PAE with both Gram-positive and Gram-negative bacteria. While T > MIC has a role in determining outcomes, the proportion of the dosing interval for which serum drug concentrations should exceed the pathogen MIC is less than for other beta-lactams. In vitro models have shown that continuous infusion is effective, as is less frequent dosing. There are few data on continuous infusion of carbapenems but some patients have been treated with once-daily dosing. Clinically, continuous infusion therapy with penicillins and cephalosporins should be considered in patients infected with susceptible Gram-negative rods not responding to conventional therapy. As an approximation, the same total daily dose should be given but a bolus intravenous injection should be give at the start of continuous infusion to ensure Css is reached rapidly. The Css may be difficult to predict and determination of serum drug concentrations may be indicated. Ideally, the Css should be calculated based on the MIC of the potential pathogen and may be higher or lower than the Css achieved by a conventional daily dose.
TL;DR: Midazolam is a parenteral benzodiazepine with sedative, amnesic, anxiolytic, muscle relaxant and anticonvulsant properties, and its chief metabolite is 1-hydroxymethyl midrazolam.
Abstract: Midazolam is a parenteral benzodiazepine with sedative, amnesic, anxiolytic, muscle relaxant and anticonvulsant properties. The drug exerts its clinical effect by binding to a receptor complex which facilitates the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Midazolam has a faster onset and shorter duration of action than other benzodiazepines such as diazepam and lorazepam. The most serious adverse events associated with midazolam in children include hypoventilation, decreased oxygen saturation, apnoea and hypotension. It is water soluble in the commercially prepared formulation but becomes lipid soluble at physiological pH and can then cross the blood brain barrier. It is metabolised in the liver by the cytochrome P450 system, and its chief metabolite is 1-hydroxymethyl midazolam. The latter is conjugated to the glucuronide form, and it has only minimal biological activity. Midazolam is excreted primarily by the kidney. Its half-life in children over 12 months is reported to be 0.8 to 1.8 hours, with a clearance of 4.7 to 19.7 ml/min/kg. Doses given to children must be calculated on a mg/kg basis. For children 6 months to 5 years of age the initial dose is 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg titrated slowly may be necessary to achieve the desired endpoint. For children 6 to 12 years of age the initial dose is 0.025 to 0.05 mg/kg with a total dose up to 0.4 mg/kg to achieve the desired end-point.
TL;DR: The pharmacokinetic profiles of nimesulide and M1 in children and the elderly did not differ from that of healthy young individuals, and a dose reduction is required in patients with hepatic impairment.
Abstract: Nimesulide is a selective COX-2 inhibitor used in a variety of inflammatory, pain and fever states. After healthy volunteers received oral nimesulide 100 mg in tablet, granule or suspension form the drug was rapidly and extensively absorbed. Mean peak concentrations (Cmax) of 2.86 to 6.50 mg/L were achieved within 1.22 to 2.75 hours of administration. The presence of food did not reduce either the rate or extent of nimesulide absorption. When nimesulide was administered in the suppository form, the Cmax was lower and occurred later than after oral administration; the bioavailability of nimesulide via suppository ranged from 54 to 64%, relative to that of orally administered formulations. Nimesulide is rapidly distributed and has an apparent volume of distribution ranging between 0.18 and 0.39 L/kg. It is extensively bound to albumin; the unbound fraction in plasma was 1%. The unbound fraction increased to 2 and 4% in patients with renal or hepatic insufficiency. With oral administration, the concentrations of nimesulide declined monoexponentially following Cmax. The estimated mean terminal elimination half-life varied from 1.80 to 4.73 hours. Excretion of the unchanged drug in urine and faeces is negligible. Nimesulide is largely eliminated via metabolic transformation and the principal metabolite is the 4'-hydroxy derivative (M1). Minor metabolites have been detected in urine and faeces, mainly in a conjugated form. Pharmacological tests in vivo have shown that the metabolites are endowed with anti-inflammatory and analgesic properties, although their activity is lower than that of nimesulide. Excretion in the urine and faeces accounted for 50.5 to 62.5% and 17.9 to 36.2% of an orally administered dose, respectively. The total plasma clearance of nimesulide, was 31.02 to 106.16 ml/h/kg, reflecting almost exclusive metabolic clearance. The drug has a low extraction ratio, close to 0.1. With twice daily oral or rectal administration of nimesulide, steady-state was achieved within 24 to 48 hours (2 to 4 administrations); only modest accumulation of nimesulide and M1 occurred. Gender has only a limited influence on the pharmacokinetic profiles of nimesulide and M1. The pharmacokinetic profiles of nimesulide and M1 in children and the elderly did not differ from that of healthy young individuals. Hepatic insufficiency affected the pharmacokinetics of nimesulide and M1 to a significant extent: the rate of elimination of nimesulide and M1 was remarkably reduced in comparison to the rate of elimination in healthy individuals. Therefore, a dose reduction (4 to 5 times) is required in patients with hepatic impairment. The pharmacokinetic profile of nimesulide and M1 was not altered in patients with moderate renal failure and no dose adjustment in patients with creatinine clearances higher than 1.8 L/h is envisaged. Pharmacokinetic interactions between nimesulide and other drugs given in combination [i.e. glibenclamide, cimetidine, antacids, furosemide (frusemide), theophylline, warfarin and digoxin] were absent, or of no apparent clinical relevance.
TL;DR: Clinicians need to define those patients who are most likely to benefit from CPM and incorporate this into the provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value, and consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit.
Abstract: Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patientfocused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process. The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM. Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value. In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: ‘Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?’ We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit. Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to ‘treat the patient and not the level’. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.
TL;DR: Interaction studies have confirmed that when acamprosate is concomitantly administered with food, the amount absorbed is decreased and it is, therefore, contraindicated under such circumstances.
Abstract: Acamprosate is a new psychotropic drug used in the treatment of alcohol (ethanol)-dependence. Recent studies suggest that acamprosate inhibits neuronal hyperexcitability by antagonising excitatory amino acids. It is available as a 333mg enteric-coated tablet, with a recommended dosage of 1.3 g/day for patients with a bodyweight <60kg and 2 g/day for patients with a bodyweight ≥60kg. Treatment with higher dose strength tablets 2 × 500mg twice daily is bioequivalent to treatment with the 2 × 333mg 3 times daily dosage regimen.
TL;DR: Except for moderate and transient digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and seems neither responsible for gastrointestinal bleeding nor for renal, liver or haematological toxicity.
Abstract: Diacerein is a drug for the treatment of patients with osteoarthritis. This drug is administered orally as 50mg twice daily. Diacerein is entirely converted into rhein before reaching the systemic circulation. Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein glucuronide (60%) and rhein sulfate (20%); these metabolites are mainly eliminated by the kidney. The pharmacokinetics characteristics of diacerein are about the same in young healthy volunteers and elderly people with normal renal function, both after a single dose (50mg) or repeated doses (25 to 75mg twice daily). Rhein kinetics after single oral doses of diacerein are linear in the range 50 to 200mg. However, rhein kinetics are time-dependent, since the nonrenal clearance decreases with repeated doses. This results in a moderate increase in maximum plasma concentration, area under the plasma concentration-time curve and elimination half-life. Nevertheless, the steady-state is reached by the third administration and the mean elimination half-life is then around 7 to 8 hours. Taking diacerein with a standard meal delays systemic absorption, but is associated with a 25% increase in the amount absorbed. Mild-to-severe (Child Pugh’s grade B to C) liver cirrhosis does not change the kinetics of diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance <2.4 L/h) is followed by accumulation of rhein which justifies a 50% reduction of the standard daily dosage. Rhein is highly bound to plasma proteins (about 99%), but this binding is not saturable so that no drug interactions are likely to occur, in contrast to those widely reported with nonsteroidal anti-inflammatory drugs. Except for moderate and transient digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and seems neither responsible for gastrointestinal bleeding nor for renal, liver or haematological toxicity.
TL;DR: Understanding the mechanism of action and the pharmacokinetic properties of vasodilatory drugs facilitates optimal use in clinical practice and increases the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site.
Abstract: Stimulating cardiac β1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. β1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of β-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifendipine and enalapril or captopril do not pose enough of a risk to preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and β-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.
TL;DR: Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination.
Abstract: Hydroxyurea is used in the treatment of various forms of cancer, sickle-cell anaemia and HIV infection Oral absorption of the drug is virtually complete, the volume of distribution is equivalent to total body water and elimination is through both renal and nonrenal mechanisms Nonrenal elimination of hydroxyurea is characterised by Michaelis-Menten kinetics Further studies are necessary to clarify several aspects of the pharmacokinetics and pharmacodynamics of hydroxyurea: the effect of age and disease state, concentration-effect relationship, the role of therapeutic drug monitoring, and the mechanisms of renal and nonrenal elimination The recent development of improved assays for hydroxyurea should have benefits for future pharmacokinetic studies
TL;DR: Strategies to achieve optimum antibacterial concentrations in the presence of minor distrubances of the blood-CSF and blood-brain barrier include, the increased use of low toxicity antibacterials, the use of moderately lipophilic compounds, and the combination of intravenous and intraventricular administration.
Abstract: Central nervous system (CNS) infections caused by bacteria with reduced sensitivity to antibacterials are an increasing worldwide challenge. In successfully treating these infections the following conditions should be considered: (i) Antibacterials do not distribute homogeneously in the central nervous compartments [cerebrospinal fluid (CSF), extracellular space of the nervous tissue, intracellular space of the neurons, glial cells and leucocytes]. Even within the CSF, after intravenous administration, a ventriculo-lumbar concentration gradient is often observed. (ii) Valid parameters of drug entry into the CSF are the CSF: serum concentration ratio in steady state and the CSF: serum ratio of the area under the concentration-time curves (AUCCSF/AUCS). Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2 beta in serum. (iii) For most antibacterials, lipophilicity, molecular weight and serum protein binding determine the drug entry into the CSF and brain tissue. With an intact blood-CSF and blood-brain barrier, the entry of hydrophilic antibacterials (beta-lactam antibacterials, glycopeptides) into the CNS compartments is poor and increases during meningeal inflammation. More lipophilic compounds [metronidazole, quinolones, rifampicin (rifampin) and chloramphenicol] are less dependent on the function of the blood-CSF and blood-brain barrier. (iv) Determination of the minimal inhibitory concentrations (MIC) of the causative organism is necessary for optimisation of treatment. (v) For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are required. The minimum CSF concentration: MIC ratio ensuring successful therapy is unknown. Strategies to achieve optimum antibacterial concentrations in the presence of minor disturbances of the blood-CSF and blood-brain barrier include, the increased use of low toxicity antibacterials (e.g., beta-lactam antibiotics), the use of moderately lipophilic compounds, and the combination of intravenous and intraventricular administration. Antibacterials which do not interfere with bacterial cell wall synthesis delay and/or decrease the liberation of proinflammatory bacterial products, delay or inhibit tumour necrosis factor release, and may reduce brain oedema in experimental meningitis. Conclusive evidence of the reduction of neuronal damage by this approach, however, is lacking.
TL;DR: In this paper, the authors identify useful predictors (covariates) of pharmacodynamic individuality to facilitate individually optimised pharmacotherapy, which requires clinical trial designs that incorporate extensive patient profiling (such as age, gender, race, bodyweight and smoking habits).
Abstract: Variability in the relationship between pharmacological effect intensity and drug concentration (pharmacodynamics) is pronounced, usually exceeding pharmacokinetic variability. Whereas interindividual differences are large, intra-individual differences are much smaller, unless the individual experiences certain pathophysiological changes such as deterioration of renal function or progression of a chronic disease (for example, Parkinson's disease). Failure to appreciate the magnitude of interindividual variability in the pharmacodynamics of a drug can compromise fixed dose clinical trial outcomes, making the drug appear less effective or more toxic. In the face of pharmacodynamic variability it becomes important to identify useful predictors (covariates) of pharmacodynamic individuality to facilitate individually optimised pharmacotherapy. This requires clinical trial designs that incorporate extensive patient profiling, well beyond the usual short list of demographics (such as age, gender, race, bodyweight and smoking habits). In searching for predictors, it is helpful to appreciate the factors that may account for interindividual differences in the relationship between pharmacological effect intensity and drug concentration in plasma or other appropriate fluid. They include receptor density and affinity, the formation and elimination kinetics of endogenous ligands (such as the enkephalins), postreceptor transduction processes, homeostatic responses and the kinetic characteristics of transporters involved in drug transfer between fluids of distribution and the biophase. Correction of drug concentrations in plasma for protein binding, consideration of active and interactive metabolites, stereospecific assays and attention to drug distribution disequilibria are essential for successful identification of factors affecting pharmacodynamic variability. Pharmaceutical delivery systems (the 'hardware') must be combined with guidance for individualising drug dosage (the 'software' or user's manual) to provide for optimal and cost-effective pharmacotherapy.
TL;DR: Thiopental is an ultra short-acting barbiturate which remains the standard against which other induction agents are judged; it is also indicated for the therapy of brain hypoxic-ischaemia injuries and status epilepticus.
Abstract: Thiopental is an ultra short-acting barbiturate which remains the standard against which other induction agents are judged; it is also indicated for the therapy of brain hypoxic-ischaemia injuries and status epilepticus. Aspects of drug distribution that govern the onset and end of drug effect have been intensively studied to determine which parameters (in patient characteristics, diseases and administration modalities) influence effective dose and concentrations in individual patients. Thiopental has been used as a reference for pharmacokinetic and/or pharmacodynamic models in the study of rapid and short acting effect drugs. In anaesthesiology the pharmacokinetics of thiopental are described as linear; when doses and duration of treatment increase, nonlinear pharmacokinetics occur because of the saturation and/or the induction of the metabolism.
TL;DR: Lornoxicam, like other NSAIDs, appears to interact with warfarin, sulphonylureas, digoxin and furosemide, and its metabolites bind extensively to plasma albumin.
Abstract: Lornoxicam (chlorotenoxicam) is a nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class. Unlike other oxicams, lornoxicam has a relatively short plasma half-life (3 to 5 hours). Lornoxicam is eliminated following biotransformation to 5′-hydroxy-lornoxicam, which does not undergo enterohepatic recirculation. Glucoroconjugated metabolites are excreted in urine and faeces with a half-life of about 11 hours.
TL;DR: The new loop diuretic torasemide belongs to the pyridine sulfonylurea class and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema, and its pharmacokinetics are significantly influenced by liver disease.
Abstract: The new loop diuretic torasemide belongs to the pyridine sulfonylurea class. It is well absorbed and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema. This is roughly double that of the ‘classical’ loop diuretic furosemide (frusemide) [26 to 65%].
TL;DR: This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data are used for decision-making, and recommends serum concentration assay of haloperidol for investigations of nonresponse to exclude patients with pseudo-drug resistance.
Abstract: Haloperidol is the most commonly used antipsychotic drug in the therapy of acute schizophrenia. Clinicians have been using therapeutic drug monitoring in an attempt to improve clinical application of this drug. The scale of interest in this area is emphasised by the large number of studies (about 50) concerning the serum concentration-therapeutic effect relationship (SCTER) of haloperidol, including 35 studies on patients with acute schizophrenia. However, conflicting results concerning the existence and position of a therapeutic window have emerged. This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data are used for decision-making. For this purpose, a reproducible system for the evaluation of studies in this special area, a so-called total study score (TSS), was developed on an empirical basis. Thus, insufficient study design was found to be a reason for negative results. On the other hand, in spite of a great variability, the majority of studies with good design provided evidence for a significant SCTER: a bisigmoidal dependence of clinical effect on haloperidol serum concentration. The therapeutic effects of haloperidol increase at low concentrations, and the concentration has a maximum effect at about 10 micrograms/L and again decreasing at higher concentrations. The data of 552 patients also fit to this model in a single scatter plot (pseudo-r2 = 0.076, p < 0.001). The position of the therapeutic window was determined at about 5.6 to 16.9 micrograms/L. Patients treated with serum concentrations within this optimal range had a significantly better response compared with outside this range (p < 0.001, Student t-test). Therefore, a quantitative synthesis of all available data by means of effect-size analysis provides a mean effect-size (g) = 0.499 +/- 0.182 (standard deviation) for the comparison of haloperidol-treatment with serum concentrations within versus outside the therapeutic window. Thus, because of this moderate positive effect, serum concentration assay of haloperidol is recommended for patients with acute schizophrenia in a therapeutic drug monitoring programme. The modalities of haloperidol therapeutic drug monitoring in clinical practice are discussed, e.g. patient selection, method and time for serum concentration measurement, influence of premedication and comedication, interpretation of results and dose adjustment. Clinical investigations into this subject should focus on covariates which are responsible for the variability of the SCTER. Serum concentration assay is advised for investigations of nonresponse to exclude patients with pseudo-drug resistance.
TL;DR: It is not yet clear if antiandrogen are of any benefit in downstaging the extent of disease before prostatectomy and/or radiotherapy, but some evidence exist that pure antiandrogens improve survival if combined with other forms of castration.
Abstract: Prostatic cancer is the second most common cause of cancer death in males. Treatment by radical prostatectomy and radiotherapy is useful in the early stages of the disease. Whenever metastases occur, patients are usually treated by surgical (orchidectomy) or medical [gonadotropin releasing hormone (GnRH) analogue] castration. This form of treatment is, however, associated with unwanted adverse effects, such as flushing, loss of libido and potency and all patients ultimately escape therapy after a delay of 1 to 2 years. For this reason antiandrogens have been developed as another means of endocrine ablation therapy.
TL;DR: A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight, and Renal function does not affect the pharmacokinetics of mibefradil.
Abstract: Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation.